Genetic Variant IRF3:c.-141A>G (chr19-49665763-T-C) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_ModerateBA1

The NM_001571.6(IRF3):c.-141A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.277 in 1,539,912 control chromosomes in the GnomAD database, including 66,402 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.38 ( 13454 hom., cov: 32)

Exomes 𝑓: 0.27 ( 52948 hom. )

Consequence

IRF3
NM_001571.6 5_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.102

Variant links:

Genes affected

IRF3 (HGNC:6118): (interferon regulatory factor 3) This gene encodes a member of the interferon regulatory transcription factor (IRF) family. The encoded protein is found in an inactive cytoplasmic form that upon serine/threonine phosphorylation forms a complex with CREBBP. This complex translocates to the nucleus and activates the transcription of interferons alpha and beta, as well as other interferon-induced genes. The protein plays an important role in the innate immune response against DNA and RNA viruses. Mutations in this gene are associated with Encephalopathy, acute, infection-induced, herpes-specific, 7. [provided by RefSeq, Sep 2020]

IRF3 links:

BCL2L12 (HGNC:13787): (BCL2 like 12) This gene encodes a member of a family of proteins containing a Bcl-2 homology domain 2 (BH2). The encoded protein is an anti-apoptotic factor that acts as an inhibitor of caspases 3 and 7 in the cytoplasm. In the nucleus, it binds to the p53 tumor suppressor protein, preventing its association with target genes. Overexpression of this gene has been detected in a number of different cancers. There is a pseudogene for this gene on chromosome 3. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2013]

BCL2L12 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.43).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.661 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRF3	NM_001571.6 link	c.-141A>G		5_prime_UTR_variant	Exon 1 of 8	ENST00000377139.8	NP_001562.1	Q14653-1
BCL2L12	NM_138639.2 link	c.-313T>C		upstream_gene_variant		ENST00000246784.8	NP_619580.2	Q9HB09

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IRF3	ENST00000377139.8 link	c.-141A>G		5_prime_UTR_variant	Exon 1 of 8	1	NM_001571.6	ENSP00000366344.3		Q14653-1
BCL2L12	ENST00000246784.8 link	c.-313T>C		upstream_gene_variant		1	NM_138639.2	ENSP00000246784.4		A0A087WSV0

Frequencies

GnomAD3 genomes

AF:

0.380

AC:

57701

AN:

151986

Hom.:

13419

Cov.:

show subpopulations

Gnomad AFR

AF:

0.667

Gnomad AMI

AF:

0.363

Gnomad AMR

AF:

0.335

Gnomad ASJ

AF:

0.245

Gnomad EAS

AF:

0.245

Gnomad SAS

AF:

0.321

Gnomad FIN

AF:

0.230

Gnomad MID

AF:

0.386

Gnomad NFE

AF:

0.261

Gnomad OTH

AF:

0.345

GnomAD4 exome

AF:

0.266

AC:

368789

AN:

1387808

Hom.:

52948

Cov.:

AF XY:

0.267

AC XY:

181719

AN XY:

681788

show subpopulations

Gnomad4 AFR exome

AF:

0.683

Gnomad4 AMR exome

AF:

0.328

Gnomad4 ASJ exome

AF:

0.249

Gnomad4 EAS exome

AF:

0.245

Gnomad4 SAS exome

AF:

0.327

Gnomad4 FIN exome

AF:

0.234

Gnomad4 NFE exome

AF:

0.248

Gnomad4 OTH exome

AF:

0.289

GnomAD4 genome

AF:

0.380

AC:

57793

AN:

152104

Hom.:

13454

Cov.:

AF XY:

0.374

AC XY:

27835

AN XY:

74378

show subpopulations

Gnomad4 AFR

AF:

0.667

Gnomad4 AMR

AF:

0.335

Gnomad4 ASJ

AF:

0.245

Gnomad4 EAS

AF:

0.245

Gnomad4 SAS

AF:

0.319

Gnomad4 FIN

AF:

0.230

Gnomad4 NFE

AF:

0.261

Gnomad4 OTH

AF:

0.347

Alfa

AF:

0.280

Hom.:

7770

Bravo

AF:

0.399

Asia WGS

AF:

0.376

AC:

1305

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.43

CADD

Benign

8.5

DANN

Benign

0.76

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over